Patent Grant
7759364
This application claims priority to PCT/CH02/00027, filed Jan. 17, 2002, which is incorporated herein by reference.
The present invention relates to non-hydrated fexofenadine hydrochloride.
Fexofenadine hydrochloride (4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylacetic acid hydrochloride) has formula (I) below:
and is licensed by the US Food and Drug Administration (FDA) as an antihistamine, antiallergic and bronchodilator under the trade name Allegra®.
WO-A-95/31437 describes the preparation of hydrated polymorphs, or pseudo-morphs, of fexofenadine hydrochloride (form II and form IV) and their conversion to non-hydrated polymorphous forms (form I and form III) by azeotropic distillation or water-minimizing recrystallization.
WO-A-00/71124 describes amorphous, presumably non-hydrated fexofenadine hydrochloride and its preparation, a spray drying or freeze drying being carried out as the final stage.
It has now been found that non-hydrated fexofenadine hydrochloride can be prepared from fexofenadine base and hydrogen chloride in a simple and direct manner, without the need for operations such as azeotropic distillation, water-minimizing recrystallization, spray drying or freeze drying, to give the non-hydrated fexofenadine hydrochloride in the form of a novel polymorph (“form A”) or in amorphous form or in the form of a mixture of different polymorphs, depending on the reaction conditions, wherein
The compounds and radicals referred to above as “lower” appropriately contain up to eight carbon atoms. It is preferable to use acetonitrile as the lower alkyl nitrile, methanol as the lower alkanol, diethyl ether or diisopropyl ether as the di(lower alkyl) ether, ethyl acetate as the lower alkyl ester of a lower alkanecarboxylic acid, and n-hexane or n-heptane as the lower alkane.
Fexofenadine base (II) is obtainable in known manner from the hydrochloride of the corresponding keto ester, namely ethyl 4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylacetate (III).
The polymorph of fexofenadine hydrochloride obtainable according to variant (a) of the method according to the invention (“form A”) has a melting range of 153 to 156° C. (DSC) and is characterized by the following XRD data (Table 1):
This polymorph is novel and also forms a subject of the present invention. It can be used as a therapeutic active ingredient and processed to a drug containing the active ingredient and a pharmaceutically acceptable excipient. This drug is suitable as an antihistamine, antiallergic and/or bronchodilator.
Pharmaceutically acceptable excipients which can be used in the preparation of drugs are generally known and familiar to all those skilled in the art.
By virtue of their different bioavailabilities, rates of release and solubilities, different forms of a pharmaceutical active ingredient, such as novel polymorphs in particular, can be of great benefit to the patients in question since they may allow a lowering of the dosage and/or a lengthening of the dosage intervals, making it possible to reduce the costs of the medication.
The Examples which follow will illustrate the invention without in any way limiting its scope.
The XRD spectra were recorded on a Philips ADP1700 computer-controlled powder diffractometer system with automatic divergence slit and secondary monochromator (graphite). The CuKα radiation (λ (CuKα1)=0.15406 nm and λ (CuKα2)=0.15444 nm) from a copper tube (40 kV, 30 mA) was used and the spectra were recorded with Δ(2ΘN)=0.02 for a counting time of 3 s in the range 1.5°≦2Θ≦40°.
The differential scanning calorimetry (DSC) measurements were made on a METTLER DSC 821e apparatus with a start temperature of 25° C., an end temperature of 250° C. and a heating rate of 10 K min−1. Standard aluminium crucibles with perforated lids were used as the sample vessels. The amount of sample was about 5 mg in each case.
30 g of piperidine derivative III, 1.7 g of sodium borohydride and 7.4 g of sodium hydroxide were suspended in 200 g of ethanol and 44 g of water, refluxed for 3-5 h and then quenched with 10 g of acetone. The solvents were stripped off under vacuum and the residue was taken up in 200 g of water/acetone (2:1). The pH was adjusted to 5.8 to 6.0 by the addition of acetic acid, causing the fexofenadine base to crystallize out. The precipitate was filtered off, washed with water and dried under vacuum at 60° C. to give 22 g (83%) of product.
86 g of fexofenadine base were suspended in acetonitrile (700 g), and 30 g of a 20.6 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 83 g (90%) of fexofenadine hydrochloride, form A.
10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and 1.9 g of a 38.6 percent solution of hydrogen chloride in methanol were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 10.1 g (94%) of fexofenadine hydrochloride, form A.
10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and 3.7 g of a 19.5 percent solution of hydrogen chloride in ethyl acetate were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 9.8 g (91%) of fexofenadine hydrochloride, form A.
10.0 g of fexofenadine base were suspended in n-heptane (90 g), and 4.02 g of a 17.9 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with n-heptane and dried under vacuum at 100° C. to give 9.7 g (90%) of amorphous fexofenadine hydrochloride.
10.0 g of fexofenadine base were suspended in tert-butyl methyl ether (90 g), and 4.0 g of a 17.9 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with tert-butyl methyl ether and dried under vacuum at 100° C. to give 10.5 g (98%) of amorphous fexofenadine hydrochloride.
5.1 g of fexofenadine base were suspended in acetonitrile (39 g). 0.4 g of hydrogen chloride was passed into the suspension at −10 to −12° C., after which the mixture was heated at the reflux temperature for 1.5 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 00° C. to give 5.1 g (92%) of fexofenadine hydrochloride in the form of a mixture of different polymorphs.
| Number | Date | Country | Kind |
|---|---|---|---|
| 329/01 | Feb 2001 | CH | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/CH02/00027 | 1/17/2002 | WO | 00 | 3/24/2005 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO02/066429 | 8/29/2002 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 4254129 | Carr et al. | Mar 1981 | A |
| 6613906 | Davies et al. | Sep 2003 | B1 |
| Number | Date | Country |
|---|---|---|
| WO 9531437 | Nov 1995 | WO |
| WO 0071124 | Nov 2000 | WO |
| WO 0194313 | Dec 2001 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050165056 A1 | Jul 2005 | US |
